This application is in response to the RFA-ES-06-008: Manufactured nanomaterials: Physicochemical principles of biocompatibility and toxicity. Recent advances in nanotechnology have enabled fabrication of novel nanoconstructs with potential commercial and biomedical applications. Some promising nanoconstructs include dendrimers and silica nanoparticles. These nanoconstructs can be fabricated with discrete, well-defined monodisperse size, shape and surface properties. However little is known about the interactions of these particles with mammalian systems including their potential to cause toxicity. The focus of this application is on systematically evaluating the influence of size, geometry, porosity and surface functionality of dendritic as well as silica nanoparticles on their toxicity and cellular uptake. Three Specific Aims are proposed: 1. Preparation and characterization of dendrimers, porous silica nanoparticles, and silica nanotubes with discrete variations in size, charge and surface chemistry to regulate biocompatibility. 2. In vitro evaluation of toxicity, biocompatibility and mechanisms of uptake of the prepared nanomaterials as a function of physicochemical properties. 3. In vivo evaluation of biodistribution and pharmacokinetics of the nanomaterials and their subsequent correlation with physicochemical properties, toxicity and biocompatibility.